Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP

被引:108
作者
Labno, CM
Lewis, CM
You, DQ
Leung, DW
Takesono, A
Kamberos, N
Seth, A
Finkelstein, LD
Rosen, MK
Schwartzberg, PL
Burkhardt, JK
机构
[1] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[2] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[3] NHGRI, NIH, Bethesda, MD 20892 USA
[4] Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA
[5] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
关键词
D O I
10.1016/j.cub.2003.08.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse [1]. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes [2]. Since T cells from Rik-/-, Itk-/-, and Rik-/- X Itk-/- mice have defects in signaling and development [3], we asked whether Itk or Rik function in actin polymerization at the immune synapse. We find that Itk-/- and Rik-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse.
引用
收藏
页码:1619 / 1624
页数:6
相关论文
共 29 条
[1]   Identification of Itk/Tsk Src homology 3 domain ligands [J].
Bunnell, SC ;
Henry, PA ;
Kolluri, R ;
Kirchhausen, T ;
Rickles, RJ ;
Berg, LJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (41) :25646-25656
[2]   The regulation of actin remodeling during T-cell-APC conjugate formation [J].
Cannon, JL ;
Burkhardt, JK .
IMMUNOLOGICAL REVIEWS, 2002, 186 :90-99
[3]   WASP recruitment to the T cell:APC contact site occurs independently of Cdc42 activation [J].
Cannon, JL ;
Labno, CM ;
Bosco, G ;
Seth, A ;
McGavin, MHK ;
Siminovitch, KA ;
Rosen, MK ;
Burkhardt, JK .
IMMUNITY, 2001, 15 (02) :249-259
[4]   Phosphorylation of tyrosine enhances the ability of WASp to stimulate actin polymerization and filopodium formation [J].
Cory, GOC ;
Garg, R ;
Cramer, R ;
Ridley, AJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (47) :45115-45121
[5]   Allergy-associated polymorphisms of the FcεRIβ subunit do not impacts two amplification functions [J].
Donnadieu, E ;
Cookson, WO ;
Jouvin, MH ;
Kinet, JP .
JOURNAL OF IMMUNOLOGY, 2000, 165 (07) :3917-3922
[6]   Xid-like phenotypes:: A B cell signalosome takes shape [J].
Fruman, DA ;
Satterthwaite, AB ;
Witte, ON .
IMMUNITY, 2000, 13 (01) :1-3
[7]   Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor [J].
Grasis, JA ;
Browne, CD ;
Tsoukas, CD .
JOURNAL OF IMMUNOLOGY, 2003, 170 (08) :3971-3976
[8]   Tyrosine phosphorylation of the Wiskott-Aldrich Syndrome protein by Lyn and Btk is regulated by CDC42 [J].
Guinamard, R ;
Aspenström, P ;
Fougereau, M ;
Chavrier, P ;
Guillemot, JC .
FEBS LETTERS, 1998, 434 (03) :431-436
[9]   Lck regulates Vav activation of members of the Rho family of GTPases [J].
Han, JW ;
Das, B ;
Wei, W ;
VanAelst, L ;
Mosteller, RD ;
Khosravifar, R ;
Westwick, JK ;
Der, CJ ;
Broek, D .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (03) :1346-1353
[10]   Influence of the c terminus of Wiskott-Aldrich syndrome protein (WASp) and the Arp2/3 complex on actin polymerization [J].
Higgs, HN ;
Blanchoin, L ;
Pollard, TD .
BIOCHEMISTRY, 1999, 38 (46) :15212-15222